The enteric nervous system is a key player in many functions of the gastrointestinal tract, such as transport, digestion and absorption of nutrients and defense against dietary toxins and antigens, and it has been more and more implicated in a number of gastrointestinal diseases. Although the enteric nervous system can act autonomously for local control, its integrative functions are strongly modulated by the central nervous system, in particular via the vagus nerve. Vagal modulation of gastrointestinal function is thus one of the mechanisms by which, on one hand, external and internal events can lead to adaptive and physiologically beneficial effects and, on the other hand, emotional states such as stress can lead to maladaptive effects and disease. This proposal is designed to define the interface between vagal outflow and enteric neurons, the functional units of the enteric nervous system. Some of the questions that should be answered by the proposed studies are: Is vagal outflow organized in a function-specific manner? Is specificity encoded by the neurochemical phenotype of vagal preganglionic neurons of postganglionic, enteric neurons? What are the characteristics of so-called "command neurons" in the small intestine? What is the functional role of peptides and other co-transmitters in the vagal outflow system? Modern anatomical, molecular- neurochemical, and functional approaches at the cellular and tissue level, as well as an innovative new method to study integrated gut motility will be used. The results will identify the underlying neural substrate and characterize the functional effects of vagal modulation of key gut segments such as the stomach, lower esophageal and pyloric sphincters, small intestine and colon. The findings will lead to new insights about central neural control of normal gastrointestinal function. They may also provide important new clues concerning the effects of physical and emotional stress as well as alcohol on the development of gastric and duodenal lesions and concerning the problem of human gastroesophageal reflux. Finally, the proposed studies will help understand the neural component in the many gastrointestinal motility disorders, gastric stasis induced by acute bacterial infection, and in the longer-term sequelae of inflammatory bowel disease.